A number of mutations responsible for causing the blinding human retinal degenerative diseases categorized as retinitis pigmentosa (RP) have been identified These include over 50 different mutations in the rhodopsin gene, several in the peripherin rds gene and several in the gene encoding beta-cGMP phosphodiesterase (betaPDE)(1-11). The common denominator of these mutations is that they involve genes expressed primarily in the photoreceptor cells of the neural retina. Animal models exist for RP and the responsible mutations have been identified in several of these. Retinal degeneration leading to blindness occurs in the rd/rd mouse and the rcd1/rcd1 dog. In each case, the disease is due to a mutation in the gene encoding betaPDE which abolishes the function of this enzyme (12, 13). Similar mutations in betaPDE have also been identified in several human patients with autosomal recessive RP (11). Two recent findings in our laboratory suggest that it may now be possible to treat hereditary retinal degenerations, such as those resulting from null mutations in betaPDE, with genetic therapy: 1) We have demonstrated that recombinant replication-defective adenoviruses can be used to introduce reporter genes in an efficient and stable fashion into terminally differentiated photoreceptors in vivo (17, 18); 2) Our recent isolation and identification of photoreceptor-specific (opsin) promoters (14-16) now provides a means with which to introduce functional genes specifically into photoreceptor cells. The research proposed here aims to determine whether introduction of wild-type betaPDE into photoreceptors of the rd/rd mouse and the rcd1/rcd1 dog can reverse or slow the degeneration. Therapeutic and other effects of wild-type betaPDE will he assessed qualitatively and quantitatively after adenoviral-mediated gene transfer. Use of mutant strains from diverse species, canine and murine, will give generality to our result. The ability to introduce stable exogenous genes into adult mammalian retina could ultimately pave the way for genetic therapy as a treatment for blinding and currently incurable inherited retinal degenerations such as RP.